The use of high viscosity grade hydrophilic and the hydrophobic polymers to produce extended or controlled release pharmaceutical composition is known in the art. For extending the release, the tablet comprising the drug also comprises of high viscosity grade hydrophilic polymer. If required the tablets are coated with hydrophobic polymer and pore forming agent. As soon as the solid dosage form comes in contact with the surrounding media, pores are formed and the drug is diffused through these pores. The media enters the tablet core and results into the hydration of the polymer which also controls the release of the drug. Control of the rate of release benefits therapy by producing constant blood plasma levels of the active ingredient and by decreasing the frequency of administration, thereby improving the patient compliance to the dosage regimen. The present invention provides a pharmaceutical composition of extended release tablets of Levetiracetam suitable for once daily administration to human subjects.
It is known that the absorption and bioavailability of any particular therapeutic agent can be affected by numerous factors when dosed orally. Such factors include the presence of food in the gastrointestinal (GI) tract because, in general, the gastric residence time of a drug is usually significantly longer in the presence of food than in the fasted state. If the bioavailability of a drug is affected beyond a certain point due to the presence of food in the GI tract, the drug is said to exhibit a “food effect”. Food effects are important inasmuch as, when a drug exhibits an adverse food effect, there is risk associated with administering it to a patient who has eaten recently. The risk derives from the potential that absorption into the bloodstream may be adversely affected to the point that the patient risks insufficient absorption to remediate the condition for which the drug was administered.
Levetiracetam is chemically named as (−)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide with molecular formula C8H14N2O2 and molecular weight 170.21. Levetiracetam is white to off white crystalline powder and has aqueous solubility of 104 gm/ml. It is freely soluble in chloroform (65.3 g/100 mL) and in methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble in acetonitrile (5.7 g/100 mL) and practically insoluble in n-hexane. Levetiracetam is described in the U.S. Pat. Nos. 4,837,223, 4,943,639 and 6,107,492.
Levetiracetam is indicated as adjunctive therapy in the treatment of partial onset seizures in adults with epilepsy. The precise mechanism(s) by which Levetiracetam exerts its antiepileptic effect is unknown and does not appear to derive from any interaction with known mechanisms involved in inhibitory and excitatory neurotransmission. Levetiracetam is rapidly absorbed with the oral bioavailability of 100%. Food does not affect the extent of absorption of Levetiracetam but it decreases cmax by 20% and delays Tmax by 1.5 hours. The pharmacokinetics of Levetiracetam are linear over a dose range of 500-5000 mg, with steady state kinetics being achieved 2 days after multiple twice daily dosing. It is less than 10% bound to plasma proteins. Levetiracetam has plasma elimination half life of 7±1 hr with the volume of distribution of 0.6 L/Kg. The total body clearance is 0.9 ml/min/kg and the renal clearance is 0.6 ml/min/kg. Its elimination is correlated with creatinine clearance. There is no age, gender, race or circadian effect.
Presently Levetiracetam is administered to adults as conventional immediate release tablets. The current dosing regimen includes twice daily administration. Levetiracetam is available as an immediate release and is approved for sale in various countries including the United States of America under the brand name KEPPRA™ (UCB Pharma.). KEPPRA™ is available in 250, 500 and 750 mg strengths as the immediate release tablet formulation.
In the Biopharmaceutics Classification System, it belongs to Class I since it is highly soluble (1.04 g/ml), highly permeable (F>90%) and >85% of the tablet amount released in 15 minutes in three different pH media. Clinically, it does not belong to narrow therapeutic class because it has a relatively low order of toxicity and a relatively high therapeutic index.
The twice daily dosing regimen for immediate-release Levetiracetam tablets is well tolerated with few incidences of neuropsychiatric adverse events like, somnolence, fatigue, coordination difficulties and behavioral abnormalities. The adverse effects are proportionate to the drug plasma level and therefore for improving the therapeutic efficacy, reducing incidences of adverse events and enhancing patient compliance an extended release once-daily regimen is explored in the present invention.
WO 01/51033 provides for a Solid pharmaceutical compound that can be administered orally, permitting controlled release of at least one active substance which can be Levetiracetam consisting of a homogeneous mixture comprising active substance, at least one matrix excipient between 5 and 95% by weight in relation to total weight of the compound, selected among the inert matrices, the hydrophilic, or lipid matrices, mixtures of inert and lipidic matrices mixture of hydrophilic and inert matrices; at least one entero-soluble polymer between 2 and 50% by weight in relation to the total weight of the compound and at least one alkalinizing agent soluble in a aqueous phase under conditions of physiological pH, of at least 0.5 to 50% by weight in relation to the total weight of the compound.
WO 03/101428 provides for a method for the manufacture of a pharmaceutical compound with retarded release of the active principle, which can be Levetiracetam. A mixture of active substance and the polymer that provides the retarded release are compressed by putting them through two rollers that have a temperature of more than 40° C. and compaction force is exerted on it of more than 15 to 40 kN/cm roller width. The compressed mixture is powdered to the desired particle size and if required the process is repeated.